Cystic Fibrosis (CF) is the most common lethal autosomal recessive disease in Caucasians and is caused by defects in the cystic fibrosis conductance regulator (CFTR) chloride channel. Clinically relevant tissues affected in CF include the lung, pancreas, liver, intestine, and gallbladder. The progression of life-threatening lung disease can be significantly impacted by disease in other organs, through metabolic and endocrine abnormalities that are only poorly understood. For example, pancreatic disease in CF patients leads to diabetes mellitus in 10-15% of patients and these patients die earlier than other CF patients. Cystic fibrosis- related diabetes (CFRD) is clinically distinct from type 1 and type 2 diabetes, and can significantly impact the nutritional and pulmonary health of CF patients. CFRD is largely due to insulin deficiency, but insulin sensitivity and hepatic glucose production can also be altered. Metabolic disease in CFRD can be compounded by defects in intestinal absorption and by chronic inflammation, leading to a failure to thrive and a rapid decline in lung function. A lack of animal models for CFRD has hampered basic research on the pathophysiology of this disease. At the University of Iowa, we have generated two new models of CF in the ferret and pig. Unique to the CFTR-knockout ferret model is a predisposition to developing CFRD. Both the pig and ferret CF models retain the pancreatic, liver, intestinal, and lung abnormalities seen in human CF patients, and differ from CFTR-deficient mice, in which the primary affected organ is the intestine. The purpose of the proposed R24 seeding grant is to build a team of investigators and interdisciplinary relationships that will enable us to characterize the metabolic and endocrine defects observed in CF ferrets and define its relationship to CFRD. Dissection of disease processes in the CF ferret model requires expertise in a wide range of areas including: 1) comparative pathology, 2) species-specific clinical assay development, 3) bile-acid and cholesterol/lipid homeostasis, 4) lipid absorption by the intestine, 5) glucose and lipid homeostasis, 6) comparative bacteriology, and 7) comparative biology of CFTR functions and CF- related organ disease. This grant would provide the funds necessary for developing collaborative interactions between five team members at the University of Iowa and four at other institutions. Funds are requested for distribution through four principal investigators at the University of Iowa, via associated subcontracts, and would be used to establish working relationships, preliminary data, and a well-defined R24 research plan.